tbuckley/cabot-search huggingface dataset:
Use of 2,6-diaminopurine as a potent suppressor of UGA premature stop codons in cystic fibrosis
Authors: Catherine Leroy, Sacha Spelier, Nadège Charlene Essonghe, Virginie Poix, Rebekah Kong, Patrick Gizzi, Claire Bourban, Séverine Amand, Christine Bailly, Romain Guilbert, David Hannebique, Philippe Persoons, Gwenaëlle Arhant, Anne Prévotat, Philippe Reix, Dominique Hubert, Michèle Gérardin, Mathias Chamaillard, Natalia Prevarskaya, Sylvie Rebuffat, George Shapovalov, Jeffrey Beekman, Fabrice Lejeune
Journal: Molecular Therapy (2023)

Nonsense mutations are responsible for around 10% of cases of genetic diseases, including cystic fibrosis. 2,6-diaminopurine (DAP) has recently been shown to promote efficient readthrough of UGA premature stop codons. In this study, we show that DAP can correct a nonsense mutation in the Cftr gene in vivo in a new CF mouse model, in utero, and through breastfeeding, thanks, notably, to adequate pharmacokinetic properties. DAP turns out to be very stable in plasma and is distributed throughout the body. The ability of DAP to correct various endogenous UGA nonsense mutations in the CFTR gene and to restore its function in mice, in organoids derived from murine or patient cells, and in cells from patients with cystic fibrosis reveals the potential of such readthrough-stimulating molecules in developing a therapeutic approach. The fact that correction by DAP of certain nonsense mutations reaches a clinically relevant level, as judged from previous studies, makes the use of this compound all the more attractive. Nonsense mutations are responsible for around 10% of cases of genetic diseases, including cystic fibrosis. 2,6-diaminopurine (DAP) has recently been shown to promote efficient readthrough of UGA premature stop codons. In this study, we show that DAP can correct a nonsense mutation in the Cftr gene in vivo in a new CF mouse model, in utero, and through breastfeeding, thanks, notably, to adequate pharmacokinetic properties. DAP turns out to be very stable in plasma and is distributed throughout the body. The ability of DAP to correct various endogenous UGA nonsense mutations in the CFTR gene and to restore its function in mice, in organoids derived from murine or patient cells, and in cells from patients with cystic fibrosis reveals the potential of such readthrough-stimulating molecules in developing a therapeutic approach. The fact that correction by DAP of certain nonsense mutations reaches a clinically relevant level, as judged from previous studies, makes the use of this compound all the more attractive.
Social Isolation and Loneliness as Medical Issues
Authors: Julianne Holt-Lunstad, Carla Perissinotto
Journal: New England Journal of Medicine (2023)

Interview with Dr. Julianne Holt-Lunstad on the association between social connection and health. (10:44)Download A patient's level of social connection was largely treated as a personal issue until the pandemic forced us to reckon with secondary effects of social distancing and other isolating policies.
Adipokines as an important link between hidradenitis suppurativa and obesity: a narrative review
Authors: Piotr K Krajewski, Łukasz Matusiak, Jacek C Szepietowski
Journal: British Journal of Dermatology (2022)

Abstract Hidradenitis suppurativa (HS) is a chronic, recurrent, debilitating disorder of the pilosebaceous unit. Although its pathophysiology is not fully explained, inflammation seems to play an essential role in the development of HS. A link between obesity – often considered a state of chronic inflammation – and a higher prevalence of HS has been described. Nevertheless, the exact association is not well understood. Adipose tissue is a highly active endocrine organ that produces and secretes a variety of metabolically and immunologically active molecules called adipokines. The imbalances in concentrations of several adipokines in patients with HS have already been described. A shift towards the overproduction of proinflammatory adipokines (including leptin, resistin and visfatin) with the suppression of anti-inflammatory ones (adiponectin) has been noted. We conducted a review of the available data on adipokines in HS, concentrating on the described imbalances in adipokine concentrations, as well as possible implications in HS pathogenesis. Moreover, new, unstudied adipokines with possible implications in the development of HS are proposed.
Effects of ambient air pollution on outpatient visits for psoriasis in Wuhan, China: a time-series analysis
Authors: Jiajia Lan, Qiuyi Huang, Liu Yang, Yan Li, Jing Yang, Biling Jiang, Liang Zhao, Yuting Xia, Xinyu Yu, Juan Tao
Journal: British Journal of Dermatology (2022)

Psoriasis can be provoked by both external and internal factors. The effects of environmental factors on psoriasis remain unclear.To investigate the effects of air pollution on outpatient visits for psoriasis.A distributed lag nonlinear model following quasi-Poisson regression was used to evaluate the lag effects of air pollutants on psoriasis outpatient visits, adjusting for potential confounders. Stratified analyses were performed to identify potential effect modifications by sex, age and season.In total, 13 536 outpatient visits for psoriasis were recorded in Wuhan, China from 1 January 2015 to 31 December 2019. In the single-pollutant model, exposures to particulate matter (PM) smaller than 2.5 μm (PM2.5), PM smaller than 10 μm (PM10), NO2 and SO2 were found to be significantly associated with increased daily psoriasis outpatient visits. For the largest effects, a 10-μg m-3 increase in concentrations of PM2.5 (lag1), PM10 (lag1), NO2 (lag0) and SO2 (lag3) corresponded to 0.32% [95% confidence interval (CI) 0.01-0.63], 0.26% (95% CI 0.05-0.48), 0.98% (95% CI 0.01-1.96) and 2.73% (95% CI 1.01-4.47) increases in psoriasis outpatient visits, respectively. In the two-pollutant model, only NO2 showed significant and stable effects on the outpatient visits for psoriasis.Ambient air pollution, especially NO2, appears to be significantly associated with an increased risk of outpatient visits for psoriasis in Wuhan, China. Air pollution control and exposure prevention could be effective measures to relieve the symptoms of psoriasis among these patients.
Accelerated clearance by antibodies against methoxy PEG depends on pegylation architecture
Authors: Yi-Chen Lin, Bing-Mae Chen, Trieu Thi My Tran, Tien-Ching Chang, Talal Salem Al-Qaisi, Steve R. Roffler
Journal: Journal of Controlled Release (2023)

Methoxy polyethylene glycol (mPEG) is attached to many proteins, peptides, nucleic acids and nanomedicines to improve their biocompatibility. Antibodies that bind PEG are present in many individuals and can be generated upon administration of pegylated therapeutics. Anti-PEG antibodies that bind to the PEG "backbone" can accelerate drug clearance and detrimentally affect drug activity and safety, but no studies have examined how anti-methoxy PEG (mPEG) antibodies, which selectively bind the terminus of mPEG, affect pegylated drugs. Here, we investigated how defined IgG and IgM monoclonal antibodies specific to the PEG backbone (anti-PEG) or terminal methoxy group (anti-mPEG) affect pegylated liposomes or proteins with a single PEG chain, a single branched PEG chain, or multiple PEG chains. Large immune complexes can be formed between all pegylated compounds and anti-PEG antibodies but only pegylated liposomes formed large immune complexes with anti-mPEG antibodies. Both anti-PEG IgG and IgM antibodies accelerated the clearance of all pegylated compounds but anti-mPEG antibodies did not accelerate clearance of proteins with a single or branched PEG molecule. Pegylated liposomes were primarily taken up by Kupffer cells in the liver, but both anti-PEG and anti-mPEG antibodies directed uptake of a heavily pegylated protein to liver sinusoidal endothelial cells. Our results demonstrate that in contrast to anti-PEG antibodies, immune complex formation and drug clearance induced by anti-mPEG antibodies depends on pegylation architecture; compounds with a single or branched PEG molecule are unaffected by anti-mPEG antibodies but are increasingly affected as the number of PEG chain in a structure increases.
Influence of lung cancer model characteristics on tumor targeting behavior of nanodrugs
Authors: Weixia Xu, Shengmin Yang, Linwei Lu, Qianzhu Xu, Sunyi Wu, Jianfen Zhou, Jiashen Lu, Xingyan Fan, Nana Meng, Yuan Ding, Xudong Zheng, Weiyue Lu
Journal: Journal of Controlled Release (2023)
Tailoring surface properties of liposomes for dexamethasone intraocular administration
Authors: M.D. Al-Amin, Francesca Mastrotto, Astrid Subrizi, Merve Sen, Tiina Turunen, Blanca Arango-Gonzalez, Marius Ueffing, Alessio Malfanti, Arto Urtti, Stefano Salmaso, Paolo Caliceti
Journal: Journal of Controlled Release (2023)

Diseases of the posterior eye segment are often characterized by intraocular inflammation, which causes, in the long term, severe impairment of eye functions and, ultimately, vision loss. Aimed at enhancing the delivery of anti-inflammatory drugs to the posterior eye segment upon intravitreal administration, we developed liposomes with an engineered surface to control their diffusivity in the vitreous and retina association. Hydrogenated soybean phosphatidylcholine (HSPC)/cholesterol liposomes were coated with (agmatinyl)6-maltotriosyl-acetamido-N-(octadec-9-en-1-yl)hexanamide (Agm6-M-Oleate), a synthetic non-peptidic cell penetration enhancer (CPE), and/or 5% of mPEG2kDa-DSPE. The zeta potential of liposomes increased, and the mobility in bovine vitreous and colloidal stability decreased with the Agm6-M-Oleate coating concentration. Oppositely, mPEG2kDa-DSPE decreased the zeta potential of liposomes and restored both the diffusivity and the stability in vitreous. Liposomes with 5 mol% Agm6-M-Oleate coating were well tolerated by ARPE-19 retina cells either with or without mPEG2kDa-DSPE, while 10 mol% Agm6-M-Oleate showed cytotoxicity. Agm6-M-Oleate promoted the association of liposomes to ARPE-19 cells with respect to plain liposomes, while mPEG2kDa-DSPE slightly reduced the cell interaction. Dexamethasone hemisuccinate (DH) was remotely loaded into liposomes with a loading capacity of ∼10 wt/wt%. Interestingly, mPEG2kDa-DSPE coating reduced the rate of DH release and enhanced the disposition of Agm6-M-Oleate coated liposomes in the ARPE-19 cell cytosol resulting in a more efficient anti-inflammatory effect. Finally, mPEG2kDa-DSPE enhanced the association of DH-loaded Agm6-M-Oleate coated liposomes to explanted rat retina, which reflected in higher viability of inner and outer nuclear layer cells.
CD73 Inhibitor Oleclumab Plus Osimertinib in Previously Treated Patients With Advanced T790M-Negative EGFR-Mutated NSCLC: A Brief Report
Authors: Dong-Wan Kim, Sang-We Kim, D. Ross Camidge, Catherine A. Shu, Kristen A. Marrone, Xiuning Le, Collin M. Blakely, Keunchil Park, Gee-Chen Chang, Sandip Pravin Patel, Gozde Kar, Zachary A. Cooper, Ramin Samadani, Michael Pluta, Rakesh Kumar, Suresh Ramalingam
Journal: Journal of Thoracic Oncology (2023)

CD73 is overexpressed in EGFR-mutated NSCLC and may promote immune evasion, suggesting potential for combining CD73 blockers with EGFR tyrosine kinase inhibitors (TKIs). This phase 1b-2 study (NCT03381274) evaluated the anti-CD73 antibody oleclumab plus the third-generation EGFR TKI osimertinib in advanced EGFR-mutated NSCLC.Patients had tissue T790M-negative NSCLC with TKI-sensitive EGFR mutations after progression on a first- or second-generation EGFR TKI and were osimertinib naive. They received osimertinib 80 mg orally once daily plus oleclumab 1500 mg (dose level 1 [DL1]) or 3000 mg (DL2) intravenously every 2 weeks. Primary end points included safety and objective response rate by Response Evaluation Criteria in Solid Tumors version 1.1.By July 9, 2021, five patients received DL1 and 21 received DL2. Of these patients, 60.0% and 85.7% had any-grade treatment-related adverse events (TRAEs) and 20.0% and 14.3% had grade 3 TRAEs, respectively. No dose-limiting toxicities, serious TRAEs, or deaths occurred. Four patients were T790M positive on retrospective circulating tumor DNA (ctDNA) testing; three had objective partial responses. In patients who were T790M negative in tumor and ctDNA, objective response rate was 25.0% at DL1 and 11.8% at DL2 (all partial responses); response durations at DL2 were 14.8 and 16.6 months. In patients receiving DL2, excluding those who were T790M positive by ctDNA, median progression-free survival was 7.4 months, and median overall survival was 24.8 months. DL2 was the recommended phase 2 dose.Oleclumab plus osimertinib was found to have moderate activity with acceptable tolerability in previously treated patients with advanced EGFR-mutated NSCLC.
Graphene oxide nanoarchitectures in cancer biology: Nano-modulators of autophagy and apoptosis
Authors: Afshin Taheriazam, Ghazaleh Gholamiyan Yousef Abad, Shima Hajimazdarany, Mohammad Hassan Imani, Setayesh Ziaolhagh, Mohammad Arad Zandieh, Seyedeh Delaram Bayanzadeh, Sepideh Mirzaei, Michael R. Hamblin, Maliheh Entezari, Amir Reza Aref, Ali Zarrabi, Yavuz Nuri Ertas, Jun Ren, Romina Rajabi, Mahshid Deldar Abad Paskeh, Mehrdad Hashemi, Kiavash Hushmandi
Journal: Journal of Controlled Release (2023)
Use of <scp>patient‐reported</scp> outcomes in heart failure: from clinical trials to routine practice
Authors: Gianluigi Savarese, Joann Lindenfeld, Davide Stolfo, Kirkwood Adams, Tariq Ahmad, Nihar R. Desai, Enrico Ammirati, Stephen S. Gottlieb, Mitchell A. Psotka, Giuseppe M.C. Rosano, Larry A. Allen
Journal: European Journal of Heart Failure (2023)

Heart failure (HF) is a complex syndrome that affects mortality/morbidity and acts at different levels in the patient's life, resulting in a drastic impairment in multiple aspects of daily activities (e.g. physical, mental/emotional, and social) and leading to a reduction in quality of life. The definition of disease status and symptom severity has been traditionally based on the physician assessment, while the patient's experience of disease has been long overlooked. The active participation of patients in their own care is necessary to better understand the perception of disease and the multiple aspects of life affected, and to improve adherence to treatments. Patient-reported outcomes (PROs) aim to switch traditional care to a more patient-centred approach. Although PROs demonstrated precision in the evaluation of disease status and have a good association with prognosis in several randomized controlled trials, their implementation into clinical practice is limited. This review discusses the modalities of use of PROs in HF, summarizes the most largely adopted PROs in HF care, and provides an overview on the application of PROs in trials and the potential for their transition to clinical practice. By discussing the advantages and the disadvantages of their use, the reasons limiting their application in daily clinical routine, and the strategies that may promote their implementation, this review aims to foster the systematic integration of the patient's standpoint in HF care.
Prevalence, characteristics and outcomes of older patients with hereditary versus <scp>wild‐type</scp> transthyretin amyloid cardiomyopathy
Authors: Aldostefano Porcari, Yousuf Razvi, Ambra Masi, Rishi Patel, Adam Ioannou, Muhammad U. Rauf, David F. Hutt, Dorota Rowczenio, Janet Gilbertson, Ana Martinez‐Naharro, Lucia Venneri, Carol Whelan, Helen Lachmann, Ashutosh Wechalekar, Candida Cristina Quarta, Marco Merlo, Gianfranco Sinagra, Philip N. Hawkins, Marianna Fontana, Julian D. Gillmore
Journal: European Journal of Heart Failure (2023)

Transthyretin amyloid cardiomyopathy (ATTR-CM) is often assumed to be associated with wild-type TTR genotype (ATTRwt) in elderly patients (aged ≥70), some of whom are not offered genetic testing. We sought to estimate the prevalence, clinical characteristics and prognostic implications of transthyretin (TTR) variants among elderly patients diagnosed with ATTR-CM.Data from consecutive patients over 70 years of age diagnosed with ATTR-CM at the UK National Amyloidosis Centre between January 2010 and August 2022 were retrospectively evaluated. All patients underwent clinical evaluation, biochemical tests, echocardiography and TTR genotyping. The study outcome was all-cause mortality. The study population consisted of 2029 patients with ATTR-CM (median age 79 years at diagnosis, 13.5% females, 80.4% Caucasian). Variant ATTR-CM (ATTRv-CM) was diagnosed in 20.7% (n = 421) of the study population of whom 327 (77.7%) carried V122I, 47 (11.2%) T60A, 16 (3.8%) V30M and 31 (7.3%) other pathogenic TTR variants. During a median (range) follow-up of 29 (12-48) months, ATTRv-CM was associated with increased all-cause mortality compared to ATTRwt-CM, with the poorest survival observed in V122I-associated ATTRv-CM (p < 0.001). Univariable and multivariable logistic regression analyses in those with ATTR-CM showed younger age at diagnosis (odds ratio [OR] 0.85 per year, p < 0.001), female sex (OR 2.73, p < 0.001), Afro-Caribbean ethnicity (OR 65.5, p < 0.001), atrial fibrillation (OR 0.65, p = 0.015), ischaemic heart disease (OR 0.54, p = 0.007), peripheral polyneuropathy (OR 5.70, p < 0.001) and orthostatic hypotension (OR 6.29, p < 0.001) to be independently associated with ATTRv-CM.Up to 20.7% of elderly patients with ATTR-CM have a pathogenic TTR variant. These findings support routine sequencing of the TTR gene in all patients with ATTR-CM regardless of age.
Retraction Note: CircPSMC3 suppresses the proliferation and metastasis of gastric cancer by acting as a competitive endogenous RNA through sponging miR-296-5p
Authors: Dawei Rong, Chen Lu, Betty Zhang, Kai Fu, Shuli Zhao, Weiwei Tang, Hongyong Cao
Journal: Molecular Cancer (2023)

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s12943-019-0958-6.
Suppression of Lung Cancer Malignancy by Micellized siRNA through Cell Cycle Arrest
Authors: Haejoo Kim, In‐ho Jeong, Yeol Kyo Choi, Yeon Kyung Lee, Eunyoung Moon, Yang Hoon Huh, Wonpil Im, Jun‐O Jin, Minseok Kwak, Peter Chang‐Whan Lee
Journal: Advanced Healthcare Materials (2023)

UBA6-specific E2 conjugation enzyme 1 (USE1) is frequently overexpressed in lung cancer patients. Moreover, the critical role of USE1 in the progression of human lung cancer is also indicated. As the next step, the authors aim to develop USE1-targeted therapeutic agents based on RNA interference (RNAi). In this study, a lipid-modified DNA carrier, namely U4T, which consists of four consecutive dodec-1-ynyluracil (U) nucleobases to increase the cell permeability of siRNA targeting of USE1 is introduced. The U4Ts aggregate to form micelles, and the USE1-silencing siRNA-incorporated soft spherical nucleic acid aggregate (siSNA) can be created simply through base-pairing with siRNA. Treatment with siSNA is effective in suppressing tumor growth in vivo as well as cell proliferation, migration, and invasion of lung cancer cells. Furthermore, siSNA inhibited tumor cell growth by inducing cell cycle arrest in the G1 phase and apoptosis. Thus, the anti-tumor efficacy of siSNA in lung cancer cell lines and that siSNA possesses effective cell-penetrating ability without using cationic transfection moieties are confirmed. Collectively, these results suggest that siSNA can be applied to the clinical application of RNAi-based therapeutics for lung cancer treatment.
Acute heart failure after non‐cardiac surgery: incidence, phenotypes, determinants and outcomes
Authors: Danielle M. Gualandro, Christian Puelacher, Michelle S. Chew, Henrik Andersson, Giovanna Lurati Buse, Noemi Glarner, Daria Mueller, Francisco A.M. Cardozo, Katrin Burri‐Winkler, Constantin Mork, Desiree Wussler, Samyut Shrestha, Isabelle Heidelberger, Mikael Fält, Reka Hidvegi, Daniel Bolliger, Andreas Lampart, Luzius A. Steiner, Stefan Schären, Christoph Kindler, Lorenz Gürke, Daniel Rikli, Didier Lardinois, Stefan Osswald, Andreas Buser, Bruno Caramelli, Christian Mueller
Journal: European Journal of Heart Failure (2023)

Primary acute heart failure (AHF) is a common cause of hospitalization. AHF may also develop postoperatively (pAHF). The aim of this study was to assess the incidence, phenotypes, determinants and outcomes of pAHF following non-cardiac surgery.A total of 9164 consecutive high-risk patients undergoing 11 262 non-cardiac inpatient surgeries were prospectively included. The incidence, phenotypes, determinants and outcome of pAHF, centrally adjudicated by independent cardiologists, were determined. The incidence of pAHF was 2.5% (95% confidence interval [CI] 2.2-2.8%); 51% of pAHF occurred in patients without known heart failure (de novo pAHF), and 49% in patients with chronic heart failure. Among patients with chronic heart failure, 10% developed pAHF, and among patients without a history of heart failure, 1.5% developed pAHF. Chronic heart failure, diabetes, urgent/emergent surgery, atrial fibrillation, cardiac troponin elevations above the 99th percentile, chronic obstructive pulmonary disease, anaemia, peripheral artery disease, coronary artery disease, and age, were independent predictors of pAHF in the logistic regression model. Patients with pAHF had significantly higher all-cause mortality (44% vs. 11%, p < 0.001) and AHF readmission (15% vs. 2%, p < 0.001) within 1 year than patients without pAHF. After Cox regression analysis, pAHF was an independent predictor of all-cause mortality (adjusted hazard ratio [aHR] 1.7 [95% CI 1.3-2.2]; p < 0.001) and AHF readmission (aHR 2.3 [95% CI 1.5-3.7]; p < 0.001). Findings were confirmed in an external validation cohort using a prospective multicentre cohort of 1250 patients (incidence of pAHF 2.4% [95% CI 1.6-3.3%]).Postoperative AHF frequently developed following non-cardiac surgery, being de novo in half of cases, and associated with a very high mortality.
Cost‐effectiveness of immediate initiation of dapagliflozin in patients with a history of heart failure
Authors: Robert J.H. Miller, Derek S. Chew, Lei Qin, Nowell M. Fine, Jieling Chen, John J.V. McMurray, Jonathan G. Howlett, Phil McEwan
Journal: European Journal of Heart Failure (2023)

To compare the cost-effectiveness of immediate and 12-month delayed initiation of dapagliflozin treatment in patients with a history of hospitalization for heart failure (HHF) from the UK, Canadian, German, and Spanish healthcare perspectives.A cost-utility analysis was conducted using a decision-analytic Markov model with health states defined by Kansas City Cardiomyopathy Questionnaire scores, type 2 diabetes mellitus status and incidence of heart failure (HF) events. Patient-level data for patients with prior HHF from the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial were used to inform the model inputs on clinical events and utility values. Healthcare costs were sourced from the relevant national reference databases and the published literature. Compared to standard therapy, immediate initiation of dapagliflozin decreased HHF (187 events), urgent HF visits (32 events) and cardiovascular mortality (18 events). Standard therapy was associated with lifetime costs of £13 224 and 4.02 quality-adjusted life years (QALYs). Twelve-month delayed initiation of dapagliflozin was associated with total discounted lifetime costs and QALYs of £16 660 and 4.61, respectively, compared to £16 912 and 4.66, respectively, for immediate initiation. Compared to standard therapy, immediate and 12-month delayed initiation of dapagliflozin yielded an incremental cost-effectiveness ratio (ICER) of £5779 and £5821, respectively. Compared to 12-month delayed initiation, immediate initiation of dapagliflozin had an ICER of £5263. Results were similar from the Canadian, German, and Spanish healthcare perspectives.Both immediate and 12-month delayed initiation of dapagliflozin are cost-effective. However, immediate initiation provides greater clinical benefits, with almost 10% additional QALYs gain, compared to 12-month delayed initiation of dapagliflozin and should be considered standard of care.